Histone deacetylase inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and...

Area of Science:

• Ophthalmology
• Molecular Biology
• Pharmacology

Background:

• Retinal angiogenesis is crucial for vision but can lead to disease when dysregulated.
• Histone deacetylase (HDAC) inhibitors are known to suppress angiogenesis by targeting the VEGF-mTORC1 pathway.
• Understanding the precise mechanisms of HDAC inhibitors in retinal angiogenesis is essential for therapeutic development.

Purpose of the Study:

• To investigate the underlying mechanisms by which HDAC inhibitors suppress retinal angiogenesis.
• To examine the effects of valproic acid (VPA) and vorinostat on VEGF and mTORC1 signaling in neonatal mouse retinas.
• To determine the role of proteasomal degradation in HDAC inhibitor-mediated VEGF reduction.

Main Methods:

• Neonatal mice were treated with VPA, vorinostat, or vehicle from postnatal day 0 to 3.
• Retinal vascularization, cell proliferation, VEGF expression, and mTORC1 activity (phosphorylated S6) were assessed at postnatal day 4.
• The effect of the proteasome inhibitor MG132 on VEGF expression was evaluated.

Main Results:

• VPA and vorinostat treatment significantly delayed retinal vascularization and reduced proliferating vascular cells.
• HDAC inhibitors decreased VEGF expression on the retinal surface and reduced mTORC1 activity in endothelial cells.
• MG132 partially reversed the reduction in VEGF expression caused by VPA and vorinostat, indicating proteasomal involvement.

Conclusions:

• HDAC inhibitors suppress retinal angiogenesis by inhibiting endothelial cell proliferation and reducing VEGF levels.
• The mechanism involves accelerated VEGF protein degradation mediated by the proteasome.
• These findings highlight a proteasome-dependent pathway for HDAC inhibitor action in regulating retinal neovascularization.